In a randomised, phase III LMS04 study, benefit in progression-free survival (PFS) and improved overall survival (OS) was achieved with a doxorubicin plus trabectedin induction, followed by maintenance trabectedin, as compared with standard doxorubicin monotherapy regimen. These results support earlier evidence from the phase II LMS02 study for the potential of this combination therapy in the first-line treatment of advanced or metastatic leiomyosarcoma.
The LMS04 findings show the superior efficacy of the combination therapy over treatment with doxorubicin alone with the median OS of 33 months in the doxorubicin–trabectedin group versus 24 months in the doxorubicin group, and double longer PFS with the combination therapy, 12 versus 6 months, as compared in the doxorubicin group. The study results are published by Dr. Patricia Pautier of the Département de Médecine, Institut Gustave-Roussy in Villejuif, France and colleagues on 4 September 2024 in The New England Journal of Medicine.
The authors wrote in the background that leiomyosarcomas account for nearly one quarter of all soft-tissue sarcomas, which occur predominantly in uterine locations and are characterised by not so favourable prognosis in metastatic or locally advanced stages. Despite clinical behaviour and individual genetic variants heterogeneity, the systemic chemotherapy regimen for metastatic soft-tissue sarcoma subtypes has remained largely unchanged, with doxorubicin monotherapy as the standard first-line treatment since its efficacy was first shown in 1973. Subsequent studies exploring various drug combinations, including those with doxorubicin, showed that combination therapies have yet to surpass doxorubicin monotherapy in terms of OS.
For metastatic leiomyosarcoma, second-line treatment such as trabectedin, gemcitabine, or dacarbazine has led to an objective response in 4-10% of patients, with a median PFS of 3-5 months and a median OS of approximately 12 months. Few studies have investigated first-line treatment in trial populations that included only patients with metastatic leiomyosarcoma. The LMS02 and LMS04 studies investigated doxorubicin plus trabectedin as first-line therapy in patients with metastatic or relapsed leiomyosarcoma, and another trial investigated combination therapy with gemcitabine, docetaxel, and bevacizumab in patients with uterine leiomyosarcoma.
Phase II LMS02 study of doxorubicin plus trabectedin as first-line treatment for metastatic or locally advanced leiomyosarcoma, showed promising outcomes in terms of response, disease control, PFS, and OS. The results of the T-DIS study supported the continued use of trabectedin until disease progression in patients with metastatic soft-tissue sarcoma who did not have disease progression after six cycles.
Prompted by these findings, the investigators from the French Sarcoma Group initiated the multicentre, phase III LMS04 study to compare doxorubicin alone with doxorubicin plus trabectedin followed by maintenance trabectedin as first-line therapy in patients with metastatic or unresectable uterine or extrauterine leiomyosarcomas who had not received chemotherapy previously.
As previously reported, the study primary endpoint PFS assessed by independent central review was significantly longer with the combination therapy than with doxorubicin alone, with a median of 12.2 versus 6.2 months (adjusted hazard ratio [HR] for progression or death 0.41, 95% confidence interval [CI] 0.29 to 0.58; p < 0.001). The incidence of side effects was higher with the combination therapy, although these effects were manageable.
Long-term follow-up data are now available, and the study team reports in the latest article the findings of the final analysis in the LMS04 study, with data on OS and survival free from second progression and updated data on PFS.
Patients were randomly assigned to receive either six cycles of single-agent doxorubicin or six cycles of doxorubicin plus trabectedin, with continued trabectedin as maintenance therapy in patients in the doxorubicin–trabectedin group who did not have disease progression. Surgery to resect residual disease was allowed in each group after six cycles of therapy. Analyses of study primary endpoint PFS and secondary endpoint OS were adjusted for two stratification factors, particularly tumour origin site (uterine versus soft tissue) and disease stage (locally advanced versus metastatic).
A total of 150 patients underwent randomisation. At a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients had died, of whom 47 in the doxorubicin–trabectedin group and 60 in the doxorubicin group. The median OS was longer in the doxorubicin–trabectedin group, 33 months (95% CI 26 to 48) versus 24 months in the doxorubicin group (95% CI 19 to 31); the adjusted HR for death was 0.65 (95% CI 0.44 to 0.95).
Consistent with earlier reports, PFS was longer in the doxorubicin–trabectedin group, 12 months (95% CI 10 to 16) versus 6 months in the doxorubicin group (95% CI 4 to 7); the adjusted HR ratio for progression or death was 0.37 (95% CI 0.26 to 0.53).
The incidence of adverse events and the percentage of patients with dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone.
The authors commented that a specific focus on leiomyosarcoma in this study is relevant because trials involving patients with mixed histologic characteristics often dilute the potential benefits in distinct sarcoma subtypes. The median OS of 33 months observed in the doxorubicin–trabectedin group in this study establishes a benchmark. This outcome may be a result of the efficacy of the initial chemotherapy regimen as well as the effects of subsequent treatments, including surgery, which was more feasible after combination therapy than after monotherapy owing to higher percentage of patients with a response and maintenance treatment with trabectedin.
The longer time to second disease progression with the combination therapy than with monotherapy, despite a substantial percentage of patients in the doxorubicin group receiving trabectedin after disease progression (59% of the patients in the context of second-line or subsequent treatment), reinforces the potential benefits of using an effective combination therapy as early as possible in the disease course rather than waiting for sequential treatment to manage progressing sarcoma. An ongoing study of a combination of doxorubicin and lurbinectedin induction followed by lurbinectedin maintenance, as compared with doxorubicin alone, will perhaps confirm the strategy with a lower incidence of side effects.
Other strategies of combination therapy with doxorubicin and immune checkpoint inhibitors are being tested (e.g. doxorubicin with APX005M, and ontorpacept plus doxorubicin followed by ontorpacept monotherapy) to enhance the control of the disease in patient populations with certain histologic subtypes, such as leiomyosarcomas. Options that are being tested in the context of second-line and later therapies as deregulation in DNA damage repair pathways, especially homologous recombination repair, or PI3K inhibitors may be more specifically active in leiomyosarcomas than in other subtypes and could perhaps be tested later in the context of first-line therapy for metastatic disease.
The authors commented that in the context of drug development for sarcoma management, the LMS04 study results advocate for a more nuanced approach, based on histologic features. The study results support the use of doxorubicin plus trabectedin for the first-line treatment of patients with advanced or metastatic leiomyosarcomas, offering hope for improved outcomes in this challenging disease.
In an accompanied editorial, Dr. Robert S. Benjamin of the Department of Sarcoma Medical Oncology, University of Texas M.D. Anderson Cancer Center in Houston, TX, US wrote that the current article is the culmination of a methodical series of studies by the French Sarcoma Group on the combination of doxorubicin and trabectedin that started nearly 20 years ago. After more than 50 years of single-agent doxorubicin, a true step forward has been taken, and antiquated single-agent chemotherapy is no longer needed.
The sarcoma community should expect a series of similar trials in other sarcomas in which trabectedin has shown activity but it may be too late. Given how long it took to get to this point, the EU period of orphan medicinal product exclusivity has already lapsed, and the US patent on trabectedin is set to expire in 2028. Thus, neither PharmaMar, the manufacturer in Spain, nor Janssen, the company licensed to sell trabectedin in the United States, have the financial incentive to support such trials, even to merely provide the drug or to modify the label such that insurance will cover the drug costs for future development. Hopefully, guideline modification will lead to insurance coverage for trabectedin for previously untreated patients with soft-tissue sarcoma, which will permit further investigation of this important new treatment combination according to the editorialist.
The study was previously presented in part at the ESMO 2021 and 2023 Annual Congresses.
The study was supported by PharmaMar, Institut Gustave-Roussy, and the French Sarcoma Group.
References
- Pautier P, Italiano A, Piperno-Neumann S, et al. for the French Sarcoma Group. Doxorubicin–Trabectedin with Trabectedin Maintenance in Leiomyosarcoma. N Engl J Med 2024;391:789-99.
- Benjamin RS. A Late-Arriving but Welcome Advance in Sarcoma Therapy. N Engl J Med 2024;391:854-855.